Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.

Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling. Am J Physiol Endocrinol Metab. 2020 Aug 10;: Authors: Muniyappa R, Chen H, Montagnani M, Sherman A, Quon MJ Abstract Previously, we have used mathematical modeling to gain mechanistic insight into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase-dependent (PI3K) insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data independent of those used for model development. Simulations of pathological stimuli directly impairing only ins...
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Tags: Am J Physiol Endocrinol Metab Source Type: research